EARLY ANTIBODY THERAPY CAN INDUCE SUSTAINED CELLULAR IMMUNITY TO SHIV INFECTIONS. Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have recently been used to prevent and treat lentivirus infections in humanized mice, macaques and humans. To determine whether the administration of bNAbs during the acute SHIV infection of rhesus macaques might lead to long-term control of virus replication, animals challenged with SHIVAD8-EO by mucosal or intravenous routes, received a single 2-week course of 2 potent passively transferred bNAbs (3BNC117 and 10-1074). Viremia remained undetectable for 56 to 177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. 4 additional animals maintained normal CD4+ T cell counts and very low levels of persistent viremia for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 cell per 10e6 circulating CD4+ T cells in the 6 controller macaques. Infusion of a T cell depleting anti-CD8 beta-mAb to the controller animals led to a specific decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. No reduction of NK, NKT, or gamma/delta cells was observed following this treatment. In contrast, and as a control, macaques treated for 2 or for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced a sustained rebound plasma viremia shortly following treatment interruption. We conclude that passive immunotherapy during the acute SHIV infection differs from cART in that it facilitates the emergence of potent CD8+ T cell immunity able to durably suppress virus replication. IMMUNOPROPHYLAXIS WITH A SINGLE DOSE OF DERIVATIZED ANTI-HIV NEUTRALIZING MONOCLONAL ANTIBODIES CONFERS UP TO 6 MONTHS OF PROTECTION AGAINST SHIV INFECTIONS. The introduction of 2 mutations (M428L and N434S), referred to as LS, into the FC domains of antibodies can increase their in vivo half-lives several fold by allowing them to bind to the neonatal Fc receptor and avoid rapid destruction. As a follow-up to an earlier analysis of the protective efficacy of unmodified anti-HIV-1 broadly-acting neutralizing antibodies (bNAbs), the in vivo efficacy of 3BNC117-LS and 10-1074-LS mAbs was evaluated in macaques using a repeated low-dose (RLD) challenge regimen. A single intravenous infusion of 3BNC117-LS (20 mg/kg) protected macaques against weekly SHIVAD8-EO intrarectal challenges for 11 to 23 weeks (median = 17 weeks). Administration of 10-1074-LS blocked infection for 18 to 37 weeks (median = 27weeks). To model the less intrusive subcutaneous route of bNAb injection, which would be used in a human clinical setting, the protective effect of combination 3BNC117-LS plus 10-1074-LS immunoprophylaxis (7.5 mg/kg of each mAb) was evaluated and found to delay virus acquisition 6 to 24 weeks (median = 20 weeks). The LS substitutions increased half-lives two to three-fold in macaques compared to unmodified parental antibodies. Because bNAb immunoprophylaxis must target HIV1 swarms carrying a plethora of different envelope proteins, administration of combination anti-viral neutralizing monoclonal antibodies will be the formulation of choice for human clinical use.